|Year : 2016 | Volume
| Issue : 6 | Page : 1103-1113
|Renin-Angiotensin-Aldosterone system blockade in diabetic kidney disease: A critical and contrarian point of view
Mohamed E Elrggal1, Shaaban M. S. Ahmed1, Meguid El Nahas2
1 Kidney and Urology Center, Alexandria, Egypt
2 Global Kidney Academy, Sheffield, UK
Click here for correspondence address and email
|Date of Web Publication||28-Nov-2016|
| Abstract|| |
Diabetes mellitus is the most common cause of end-stage renal disease (ESRD) worldwide. Diabetic kidney disease (DKD) is associated with high morbidity and cardiovascular mortality. A number of guidelines and recommendations have been issued over the years recommending the use of renin-angiotensin-aldosterone system (RAAS) blockade in the management of DKD. This critical analysis takes a contrarian view, based on a selection of key clinical trials in the field, to argue that albuminuria should not be considered a target for treatment but instead a surrogate marker of DKD progression. The review also challenges, through a careful and critical analysis of a number of key clinical trials, the dogma that RAAS blockade's benefits in DKD is beyond mere good blood pressure control. While selective and somewhat biased the authors make compelling arguments to shed serious doubt over the strength of the evidence upon which the current guidelines favoring the use of RAAS blockade in DKD are based.
|How to cite this article:|
Elrggal ME, Ahmed SM, El Nahas M. Renin-Angiotensin-Aldosterone system blockade in diabetic kidney disease: A critical and contrarian point of view. Saudi J Kidney Dis Transpl 2016;27:1103-13
|How to cite this URL:|
Elrggal ME, Ahmed SM, El Nahas M. Renin-Angiotensin-Aldosterone system blockade in diabetic kidney disease: A critical and contrarian point of view. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jan 24];27:1103-13. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1103/194583
| Introduction|| |
Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) in many countries.  Diabetic kidney disease (DKD) affects almost 40% of people with DM and is associated with increased morbidity and cardiovascular mortality.  Albuminuria is a major and early clinical finding in DM, with renal and cardiovascular implications. It often, but not invariably, heralds the onset of progressive diabetic nephropathy.  Furthermore, the severity of albuminuria is not significantly linked to the progression of the disease in both type 1 and type 2 DM (T1DM and T2DM). ,, Nevertheless, the use of renin-angiotensinaldosterone system (RAAS) blockers, to control hypertension and reduce albuminuria, remains one of the cornerstones of the management of diabetic nephropathy; assuming that the added control of albuminuria by these agents may impact favorably on the subsequent progression and outcome of the nephropathy.
The notion that albuminuria is a marker and possibly cause of progressive chronic kidney disease (CKD) was put forward in the early 80s. Brenner et al in Boston implied from their experimental observations on a unique strain of rodents, the Munich-Wistar rats that progressive kidney scarring and glomerulosclerosis necessitated the control of both systemic and glomerular hypertension.  Later, Remuzzi and Bertani implied that the transudation of albumin within hypertensive glomeruli would initiate glomerulosclerosis. , They later also put forward the notion of albuminuria tubule toxicity.  Subsequently, studies reported that angiotensin-converting enzyme inhibitors (ACEi), capable of reducing both types of hypertension, were more effective than other antihypertensive agents such as hydralazine and reserpine in slowing the progression of experimental CKD. While such a notion was challenged at the time,  experimental and clinical studies have been published suggesting a beneficial effect of RAAS blockade in slowing the progression of CKD in both T1DM and T2DM; using either ACEis or angiotensin receptor blockers (ARBs) or both. These agents were promoted as having the added benefit of reducing proteinuria, and therefore possibly reducing its nephrotoxicity. However, a critical analysis of the data provided by some of the key clinical trials underlying the current guidelines casts some doubts on the superiority of RAAS blockers over other agents and raises numerous questions. This review aims to explore some of these points and critically appraise some of the published and generally accepted data. It also aims to present a contrarian view to the accepted current dogma that RAAS blockade offers a therapeutic advantage in patients with CKD and more specifically DKD. This is neither a systematic review of all RAAS blockade trials in DKD nor it is a meta-analysis. We have intentionally selected the most often quoted and publicized randomized clinical trials (RCTs) to highlight some of their weaknesses and raise legitimate questions regarding their interpretation and conclusions.
| Should Albuminuria be Considered an Appropriate Surrogate Renal End Point?|| |
An important argument in favor of RAAS blockade in the management of DKD is that it reduces proteinuria/albuminuria, thus has a therapeutic advantage over other classes of antihypertensive agents that may be less effective in that respect. This assumes first, that albuminuria is a critical factor in the progression of the nephropathy, rather than just a marker of its severity or that of underlying hypertension and second, that its reduction would translate into slower DKD progression; a reliable surrogate marker of DKD progression and its management. A critical appraisal of facts shows that neither of these assumptions is fully justified.
Albuminuria has been used for decades as a predictor of DKD progression. However, more recent data have cast some doubts on its predictive value. ,, For instance, it is now recognized that microalbuminuria is neither a universal nor a sensitive or specific marker for progressive DKD.  Recent studies have found that around 20% of people with T2DM develop Stage 3 CKD while remaining normoalbuminuric.  Furthermore, the presence of microalbuminuria in T2DM may reflect microvascular disease rather than specifically DKD. Furthermore, the regression of microalbuminuria either spontaneously or following blood pressure (BP) reduction had been noted to occur in the absence of RAAS blockade in more than 50% of patients with DM.  Finally, discrepancies have been reported between interventions where albuminuria has been reduced while DKD progression was not affected or worsened. These are discussed below. Therefore, albuminuria should be considered as a biomarker of DKD progression rather than a surrogate endpoint or a treatment target. 
Below, we selected some seminal RCTs on the impact of RAAS blockade in DM and/or DKD to illustrate major shortcomings that are symptomatic of the literature and research in this field (trials summarized in [Table 1]).
|Table 1: Summary of included RCTs on the impact of RAAS blockade in DM and/or DKD and their critical appraisal.|
Click here to view
| Studies in Type 1 Diabetes Mellitus|| |
Lewis et al were the first to demonstrate, in 1993, the beneficial effect of ACE inhibitors in T1DM in a RCT using captopril versus placebo in 409 patients with T1DM with proteinuria. When compared to BP control alone, captopril showed a significant protection against renal deterioration in insulin-dependent patients with diabetic nephropathy that led to the claim that this agent was beneficial beyond the sole control of BP.  However, a close look at this study reveals a number of serious flaws and biases. First, the placebo group had much more severe albuminuria from the onset, thus predicting a worse outcome regardless of interventions. Such a randomization and selection bias seriously undermines the interpretation of the study outcome. Furthermore, both systolic and diastolic BPs were significantly lower in those receiving captopril compared to the placebo group; an elaborate statistical analysis attempted to dissociate that effect from the protection by captopril against DKD progression. Finally, glomerular filtration rate (GFR) was not measured, but the study relied instead on changes in serum creatinine levels.
Many studies followed the Lewis study over the last three decades in types 1 and 2 DKD with a range of RAAS blockers, all claiming superiority of RAAS blockers over other agents. This occurred without improvement on clinical trial design such as careful and accurate BP measurements including 24 h ambulatory BP monitoring, (24 h ABPM) that is now known to be more relevant to DM complications,  or relying on hard endpoints such as measured GFR. The latter is all the more relevant since RAAS blockers have the potential of affecting proximal tubular secretion of organic ions and creatinine making the interpretation of creatinine-based indices in patients with diabetes questionable. 
A notable exception was the RASS trial (RASS, renal and retinal effects of enalapril and losartan in type 1 diabetes); a RCT that questioned whether early ACEi or ARB would delay progression in T1DM.  The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney biopsy specimens. The study found that early RAAS blockers initiation did not delay or slow nephropathy progression in T1DM. Furthermore, ACE inhibition did not differ from placebo in the prevention of the development of microalbuminuria, while losartan increased the incidence of microalbuminuria. Neither of them changed the rate of progression of mesangial expansion over five years. This study had the advantage of relying on the hard endpoint of renal histology.
In 2001, a meta-analysis of 12 trials found that ACEi decreases the progression to macroalbuminuria in normotensive patients, with T1DM and microalbuminuria.  It could not confirm whether the therapeutic advantage was independent from BP control. Since then, many systemic reviews failed to show a therapeutic advantage of RAAS blockers over other classes of anti-hypertensive agents regarding either renal  or cardiovascular outcomes. 
| Studies in Type 2 Diabetes Mellitus|| |
In the Irbesartan Diabetic Nephropathy Trial (IDNT), 1715 hypertensive patients with T2DM and nephropathy were randomly assigned to irbesartan, amlodipine, or placebo with 2.6 years of follow-up. The irbesartan group had a 23% and 20% lower risk of composite end points (doubling of the plasma creatinine, development of ESRD , or death from any cause) than amlodipine and placebo, respectively. ,, These benefits were claimed to be independent of the observed difference in BP control between the groups, even though no attempt was made to accurately measure BP through day and night time or 24 h ABPM recordings. Of note, in IDNT, the composite cardiovascular event rate did not differ between the three groups.  IDNT, such as many RCTs on DKD progression, did not measure GFR. IDNT, such as other clinical trials in this field, relied on composite and inter-related end points; a questionable practice that could lead to statistical misinterpretation by exaggerating the real benefit of the intervention. ,
In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 1513 hypertensive patients with T2DM and nephropathy were randomly assigned to take losartan or placebo in addition to conventional antihypertensive treatments. The incidence of serum creatinine doubling and ESRD was reduced by 25% and 28%, respectively, in the losartan group compared to the placebo group. Despite these results, there are some concerns about this study,  as the placebo group had more patients with cardiovascular risks and morbidities (angina, myocardial infarction, and lipid disorders) than the losartan group, which makes randomization questionable and raises the spectrum of a selection bias. Dropout and discontinuation of treatment was very high (exceeding 40%) in RENAAL. Furthermore, as with other RCTs of this type, neither BP nor renal function was measured accurately. Furthermore, the use of composite end points as well as the premature termination of RENAAL raises statistical concerns, the former by subjecting the results to a possible spurious beneficial effects of the intervention and the latter by potentially promoting inappropriate interpretations of the results. , Besides, the question of the statistical significance of the results, it would appear that the number needed to treat to prevent one composite event over three years is high. Finally, this study failed to show any advantage of losartan over placebo in relation to cardiovascular outcomes.
In the ROADMAP study, 4447 patients with T2DM, with no overt nephropathy, were assigned to a randomized double-blinded multicenter controlled trial, to take olmesartan (40 mg once daily) or placebo in addition to other antihypertensive drugs (except ACEi or ARBs), when needed to lower BP to <130/80 mm Hg. It aimed to determine whether such intervention prevented the onset of microalbuminuria. The study showed a delay in the onset of microalbuminuria in the olmesartan group compared to the placebo group.  However, there were no benefits in terms of cardiovascular morbidity or renal function. Moreover, there were significantly more deaths in the olmesartan group, thus raising alarm over the use of these agents and/or excessive BP reduction in older people with DM. Such harm of excessive BP lowering in T2DM was confirmed in later trials, such as ACCORD, where intensive BP lowering was associated with significantly more serious adverse events. 
Using ACE inhibitors
While many studies have suggested a beneficial effect of ACE inhibitors of DKD progression, notable exceptions are seldom discussed. The ABCD Trial (Effects of Aggressive blood pressure Control in Normotensive Type 2 Diabetic Patients on Albuminuria, Retinopathy, and Strokes) was originally designed to test the effects of intensive BP control in normotensive T2DM. However, it also randomized patients to receive either enalapril or nisoldipine.  After 5.3 years of follow-up, BP was significantly lower among the intensive group (P <0.0001); however, this had little impact on CKD progression. No superiority of enalapril over nisoldipine was recorded regarding the development and progression of early diabetic complications including CKD. Only lower BP was associated with slower progression of albuminuria regardless of the agent used.
Using combination therapy
In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination therapy of ramipril plus telmisartan was compared to monotherapy in patients with DM and high cardiovascular risk. There was no difference in the composite primary outcome of death or hospitalization for cardiovascular disease, but combination therapy was associated with significantly more hypotension, syncopes, and faster rate of decline of renal function when compared to monotherapy with either ramipril or telmisartan. , However, ONTARGET was not primarily a renal outcomes trial. The recruitment process was criticized as only 4% of the enrolled patients had macroalbuminuria and 13% had microalbuminuria. Of note, ONTARGET showed that dual RAAS blockade led to worsening of kidney function in spite of a more significant reduction in albuminuria when compared to monotherapy, thus clearly dissociating a reduction in albuminuria from a protection of CKD progresssion.
VA NEPHRON D Trial: Unlike ONTARGET, this study targeted patients with T2DM, urinary albumin-to-creatinine ratio of at least 300 mg/g, and estimated GFR (eGFR) of 30-89.9 mL/min/1.73 m 2 , comparing monotherapy with losartan to combination therapy of losartan and lisinopril. The primary end points were decline in eGFR, ESRD, or death. The study had to be prematurely stopped due to excess adverse events in the combination arm of ACEi and ARB; mostly acute kidney injury (AKI) and hyperkalemia.  As with ONTARGET, dual therapy led to reduced albuminuria in spite of worsening outcomes.
A recent meta-analysis ascertained the excessive risk of adverse events such as hyperkalemia, hypotension, syncopes, and AKI affecting patients treated by combination therapy of ACEi and ARBs without a detectable reduction in the mortality rate. Overall risk to benefit ratio was clearly against the combination therapy usage. 
Combination therapy with direct renin inhibitors
Another form of combination therapy involved using the addition of direct renin inhibitor to standard therapy including ACEi or ARB.
ALTITUDE Trial (Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes) was studying the effect of adding aliskiren (a direct renin inhibitor) to standard ACEI or ARB in patients with T2DM at high cardiovascular risk. The trial was stopped prematurely after the second interim efficacy analysis due to higher reported cases of hyperkalemia and hypotension. The authors concluded that there is no evidence to support the addition of aliskiren to standard therapy with RAAS blockade in highrisk type 2 diabetic patients and it may be even harmful.  As with previous trials of combination therapy, harm was reported in spite of a significant reduction in albuminuria and BP; the latter may be harmful in older patients with T2DM and high cardiovascular risk.
| Possible Harmful Effects of RAAS Blockade|| |
Beside, the reported increases in AKI in patients treated with RAAS inhibitors alone or in combination discussed above, a recent observational study in the UK showed an increased incidence of AKI coinciding with increased use of ACE inhibitors and ARBs. This study demonstrated that 15% of the increase in AKI hospital admissions in England over 4 years may be attributable to the increased prescribing of RAAS blockade. 
Suissa et al studied a cohort of 6,102 patients with T2DM on different anti-hypertensive agents during the period of 1982-1986, were followed up till 1997.  One hundred and two patients developed ESRD and 4129 control cases were matched to them. In the first 90 days of follow-up, the adjusted hazard rate ratio of renal failure was highest for those who used for ACEi (2.5) when compared to beta blockers (0.8) and calcium channel blockers (0.7) relative to thiazide diuretics. Clearly, this early detrimental effect of ACEi in older T2DM patients may reflect an increased incidence of AKI. Afterward, the adjusted hazard rate ratio of ESRD for ACEi use in the first three years of follow-up was 0.8, but it dramatically increased to 4.2 after three years of treatment. The study concluded that ACEi increased the risk of CKD progression to ESRD in patients with T2DM. The risk was highest in those who continued beyond three years with ACEi [hazard ratio (HR) = 7.5] compared to those who used them only for three years (HR = 2.3).
| Stopping RAAS Blockade in Advanced CKD|| |
Some researchers tried to stop ACEIs and ARBs in elderly populations with advanced CKD.  This proved to be beneficial in delaying ESRD and the start of RRT with improved eGFR. This benefit was associated with increased BP levels without any reported adverse cardiovascular outcome. This observation, if confirmed, would make us rethink our approach regarding RAAS inhibition in advanced CKD population.
More recently, investigators launched a trial called "the STOP-ACE trial,"  in which they are testing the hypothesis that stopping RAASblocking agents in advanced CKD could improve eGFR at three years without affecting BP control, physical activity, hospitalization rate, cardiovascular events, or mortality. Results of this study may determine the future optimal management of advanced CKD patients.
| RAAS Blockade in Kidney Transplant Recipients|| |
RAAS blockade does not seem to confer an advantage in kidney transplant recipients. One systematic review found that ACEi or ARBs use resulted in clinically important reductions in proteinuria but failed to detect any beneficial effect on patient or graft survival.  Subsequently, a Cochrane systematic review found that calcium channel blockers may be preferred to RAAS blockers for hypertensive kidney transplant recipients.  More recently, a multicenter, double-blind, randomized, placebocontrolled trial found that treatment with ramipril compared to placebo did not lead to a significant reduction in doubling of serum creatinine, ESRD , or death in mildly proteinuric kidney transplant recipients.  Moreover, adverse events (including anemia and hyperkalemia) were more common in the ramipril group. Furthermore, mortality was higher among ramipril group, but this was not statistically significant. Of note, 47% of ramipril group had DM, a group that was thought to benefit from RAAS blockade; however, it appeared to be rather harmful at the end of the study.
| RAAS Blockade and Cardiovascular Protection|| |
Although not performed on diabetic patients, The HOPE and EUROPA trials showed beneficial effects of ACE inhibitors on cardiovascular outcomes. Ramipril significantly reduces mortality, myocardial infarction, and stroke in high-risk patients who are not known to have low ejection fraction or heart failure in the HOPE.  However, post hoc analysis of HOPE showed that when 24 h ABPM was recorded, patients treated with ramipril had a significantly lower BP, an observation that could support the observed cardioprotection. 
In general, the extent of cardiac benefits cannot be determined whether it is due to ACE inhibitors or to the lower BP, and this was clearly expressed in the Blood Pressure Lowering Treatment Trialists' Collaboration metaanalysis that showed no cardiovascular protection advantages of RAAS inhibition, but it is rather the BP lowering effect using any commonly used regimen that reduces the risk of total major cardiovascular events. 
Of interest, the recently published SPRINT study that excluded individuals with DM, while showing a protection against major cardiovascular events in individuals treated with intensive BP lowering strategy (systolic BP <120 mm Hg), did not show an advantage of any class of antihypertensive agents nor did it show an advantage for intensive BP lowering in patients with CKD. In fact, intensive BP lowering increased the incidence of AKI and CKD in those with previously normal renal function and had no effect of CKD progression in those with GFR <60 mL/min at the onset of the intervention. 
To conclude, in this review of selected but major clinical trials, we take a contrarian view to the commonly held view that RAAS blockade has a therapeutic advantage over other classes of anti-hypertensive agents in terms of renaland cardio-protection in CKD and more specifically in DKD. We show by a close and critical analysis of the published evidence that the use of RAAS-blocking agents to protect the kidneys is somewhat debatable. We show evidence that their beneficial effect is most likely dependent on their antihypertensive impact. Further, we highlight the fact that their use can be associated with harm including hypotension, syncopes, and AKI, not to mention a possible acceleration of the progression of CKD or increased mortality. While we acknowledge that the analysis we undertook is neither systematic nor comprehensive, it focused on many of the major and key clinical trials often quoted in nephrologists' clinical practice and guidelines and may be particularly relevant to the growing number of older T2DM individuals with macrovascular complications including atherosclerotic renovascular disease and associated ischemic nephropathy where RAAS blockade could cause harm in the absence of credible benefit over other antihypertensive agents.
| Acknowledgment|| |
The authors acknowledge the constructive comments of Dr. Arif Khwaja (Sheffield Kidney Institute, UK) on the manuscript as well as Dr. Mahmoud Essam Elrggal (Pharm D, Umm Al-Qura University, KSA) for his support.
Conflict of interest: None declared.
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Mohamed E Elrggal
Kidney and Urology Center, Alexandria
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